Conotoxin-derived biomimetic coiled cone-shaped peptide as ligand for selective nanodelivery to norepinephrine transporter-expressing neuroblastoma cells. (June 2022)

• Record Type: Journal Article
• Authors: Zivotska, Hana; Mokry, Michal; Rodrigo, Miguel Angel Merlos; Michalkova, Hana; Kapolkova, Katerina; Splichal, Zbynek; Stokowa-Soltys, Kamila; Milosavljevic, Vedran; Guran, Roman; Richtera, Lukas; Haddad, Yazan; Rex, Simona; Heger, Zbynek
• Is Part Of: Applied materials today. Volume 27(2022)
• Publication Date: 2022-06
• Subjects: Apoferritin -- Biomimetic peptides -- Drug delivery -- Neuroblastoma -- Norepinephrine transporter -- Targeted therapy; CD circular dichroism -- EcLHFRT apoferritin from equine spleen -- Elli ellipticine -- FBS fetal bovine serum -- ATR FT-IR Attenuated total reflectance Fourier-transform infrared spectroscopy -- hNET human norepinephrine receptor -- HPLC high performance liquid chromatography -- i-RMSD interfacial root mean square deviation -- l-RMSD ligand root mean square deviation -- MALDI-TOF matrix-assisted laser desorption/ionization-time of flight -- MD molecular dynamics -- MS mass spectrometry -- PAGE polyacrylamide gel electrophoresis -- PBS phosphate buffered saline -- RBCs red blood cells -- RMSD root mean square deviations -- SCARA5 scavenger receptor class A member 5 -- SDS sodium dodecyl sulfate -- TfR transferrin receptor 1; Materials science -- Periodicals; Materials -- Research -- Periodicals; 620.1105
• DOI: 10.1016/j.apmt.2022.101410
• Languages: English
• ISSNs: 2352-9407

Abstract

Highlights: Conotoxin-derived peptides were designed in silico and synthesized. Peptides were immobilized onto ferritin delivery vehicles loaded with ellipticine. Use of peptides led to selective cytotoxicity against hNET expressing cells. YKL-6 peptide markedly improved anticancer activity of ellipticine in vivo . Abstract: Selective drug delivery is an emerging powerful strategy, which promises efficient and safer neuroblastoma treatment in contrast to conventional therapeutic modalities. Herein, we present a newly designed apoferritin nanovehicle loaded with ellipticine and decorated with conotoxin-derived biomimetic peptide YKL-6 (sequence: YKLYKLYKLYKLYKLYKLC) to target the norepinephrine transporter (hNET), which is highly expressed on neuroblastoma cells membrane. The peptide forms a coiled cone-shape forming anti-parallel beta sheets in aggregation in vitro . Molecular docking analysis suggests electrostatic interaction mediated by lysine residues against negatively charged residues of the hNET. The assembled nanovehicles show optimal biocompatibility in healthy epithelial cells and ability to deliver ellipticine into neuroblastoma cells (UKF-NB-4 and SH-SY5Y). In our analyses, we have excluded hNET-mediated endocytosis as an uptake mechanism and demonstrated the ellipticine-triggered anti-proliferative mechanisms in neuroblastoma cells via downregulation of Bcl-2, survivin and N-myc. Finally, we present a selective inhibition of neuroblastoma growth and metastasis in vivo in an ex ovo and in ovo chicken chorioallantoic membrane assay. Overall, these findings demonstrate a great leap forward in the design of biomimetic homing peptides towards possible application in neuroblastoma nanomedicine. Graphical abstract: Image, graphical abstract